Multiple myeloma is a malignant proliferation of plasma cells that produces a monoclonal globulin. Certain complications, such as anemia, fractures, pain, renal failure, infection, and hypercalcemia, are common. Standard chemotherapies for multiple myeloma include combinations of melphalan(Drug information on melphalan) (Alkeran)-prednisone or vincristine (Oncovin)-doxorubicin (Adriamycin, Rubex)-dexamethasone (VAD), and the median survival remains 3 years. Recent investigations have focused on more intensive therapies with bone marrow or blood stem-cell support in the hope of producing more marked degrees and longer duration of disease control. Disorders closely related to multiple myeloma, including solitary plasmacytoma of bone, Waldenström's macroglobulinemia, amyloidosis, monoclonal gammopathy of unknown significance, and heavy-chain disease, must be distinguished using clinical and laboratory data. This review focuses on the etiology, diagnosis, clinical features, and therapy for multiple myeloma and other plasma-cell disorders.
In 1995, approximately 12,500 new patients will be diagnosed with multiple myeloma in the United States. The annual incidence of this disease per 100,000 population is 4.7 among white men and 3.2 among white women; among African-Americans, the frequency doubles to 10.2 in men and 6.7 in women. This racial difference presumably is due to unknown genetic factors and is not explained by socioeconomic differences. The median age of patients with multiple myeloma is approximately 70 years according to population surveys, but it is approximately 60 years based on reports of treatment trials. The incidence increases with age; the incidence in males at age 70 is almost 70 per 100,000 for African-American and 32 per 100,000 for white populations .
No predisposing events appear to be important in the etiology of multiple myeloma. Some events that have been suggested include radiation exposure (in radiologists and radium-dial workers), occupational exposure (in agricultural, chemical, metallurgical, rubber plant, pulp, and paper workers and leather tanners), and chemical exposure to benzene, formaldehyde(Drug information on formaldehyde), epichlorohydrin, hair dyes, paint sprays, and asbestos . Most of these associations have been countered by negative correlations .
Initially, it was reported that survivors of the atomic bombing of Hiroshima had a greater risk of developing myeloma, but longer follow-up data now refute any evidence of increased risk among survivors . Some reports do suggest that a lower level of prolonged radiation exposure over many years may have caused some cases of multiple myeloma among radiologists and radium-dial painters [3,4]. However, no relationship has been shown between the incidence of multiple myeloma and exposure to diagnostic x-rays or therapeutic irradiation [1,5].
Another factor associated with myeloma may be intense, prolonged exposure to benzene, such as was experienced by unprotected workers in the rubber industry . Whereas the relationship of benzene and its metabolites to the occurrence of leukemia has been accepted by many, benzene's relationship with myeloma remains unproven. With current industrial safeguards, such a relationship may never be shown.
Although myeloma is not an inherited disease, there have been numerous case reports of it in the same family . However, a case-control study revealed no significant increase in myeloma among relatives of patients with multiple myeloma, other hematologic malignancies, or other cancers .
Multiple myeloma has been the prototype of monoclonal malignancies, in this case, of plasma cells; the disease may result from a mutation of terminally differentiated B cells or even from early but committed B cells that manifest clinically as more differentiated plasma cells [8-10]. The expression of multiple markers of different cell lineages (B and T) by plasma cells supports the possibility of either an aberrant expression of unexpected phenotypes, as in other malignancies, or a stem-cell precursor from which all hematopoietic cells arise .
Multiple studies have described the cytogenetics of myeloma. Although no karyotypic abnormalities are specific, frequent aberrations of chromosomes 1 and 14, the latter containing the heavy-chain immunoglobulin gene, have been noted . In addition, specific translocations have been described, including t(11;14), t(14;18), and t(8;14). Other chromosomal abnormalities include 6q-, 7q-, 5q-, t(9;22), and 17p+. Abnormal expression of the bcl-2 protein has also been noted in patients without a t(14;18) translocation . Mutations of the ras oncogene and p53 gene mutations have been reported, especially in patients with late disease [13-15]. The ras mutation correlates with a low treatment response rate , and the p53 gene mutation has been noted in patients with extramedullary proliferation of plasma cells .
A variety of cytokines stimulate the growth of malignant plasma cells in vitro. Interleukin-6 (IL-6), considered the most important myeloma growth factor, binds to the IL-6 receptor on plasma cells, which is made up of an alpha chain (IL-6R) and a beta-transducer chain (gp130)[16,17]. IL-6 acts in concert with an extensive cytokine network (IL-1, IL-3, IL-7, IL-11, 6-colony-stimulating factor [CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF, sargramostim(Drug information on sargramostim) (Leukine)], and tumor-necrosis factor [TNF]) to promote the growth of malignant plasma cells. Other factors (alpha interferon [IFN-alfa], gamma interferon [IFN-gamma], and IL-4) appear to inhibit plasma-cell growth, and some of these cytokines may play a role in therapy.
Recent attention has been focused on the development of the multidrug resistance (MDR) phenotype in resistant myeloma, especially after prolonged therapy. The increased expression of p-glycoprotein, the MDR gene product, has been noted, particularly after high cumulative doses of vincristine and doxorubicin(Drug information on doxorubicin) .
The clinical presentation of multiple myeloma is quite variable. Bone pain, especially from compression fractures of vertebrae or ribs, is the most common symptom. Findings that suggest a diagnosis of multiple myeloma include lytic bone lesions, anemia, azotemia, hypercalcemia, and recurrent infections. However, approximately 20% of patients with multiple myeloma are free of symptoms and are diagnosed by chance.
Bone Disease: Bone lesions are due to accelerated osteoclast formation with increased resorption of areas infiltrated by plasma cells [19,20]. These changes are mediated by osteoclast-activating factors now known to consist of an extensive network of cytokines . Specifically, IL-1-beta induces and is synergistic with the bone-resorbing activity of IL-6 [20,21]. IL-6 increases natural killer-cell activity and appears to play a role in modulating the effects of TNF and IL-1 on bone .
Bone disease is best assessed by a skeletal survey. At diagnosis, nearly 70% of patients with myeloma have lytic bone lesions with or without a pathologic fracture . Nuclear bone imaging is less sensitive, because bone scan isotopes are not taken up by lytic lesions . Magnetic resonance imaging (MRI) provides greater detail of bone disease, paraspinal involvement, and epidural components; abnormalities are noted on MRI even when x-rays are normal , and they appear to be predictive of early disease progression in asymptomatic patients . Painful vertebral compression fractures, with or without cord pressure, require radiation therapy. Decompressive laminectomy is rarely necessary for cord compression, but surgery may be required for radioresistant myeloma, retropulsed bone fragments, or intervertebral disc disease when severe pain and/or disability result. Fractures of the femora or humeri require intramedullary rod fixation. The role of prophylactic bisphosphonate therapy in the reduction of osteoclastic activity and bone mineralization maintenance is under study .
Hypercalcemia: Hypercalcemia (defined as a corrected serum calcium level greater than 11.5 mg/dL) occurs in approximately 20% of patients with newly diagnosed multiple myeloma and results from progressive bone destruction. Treatment includes generous hydration and prompt combination chemotherapy, which should always include a glucocorticoid. Therapy with a regimen of VAD, which produces a rapid response, is most appropriate (Table 1). High-dose pulse dexamethasone(Drug information on dexamethasone) remains an alternative, especially for patients who require palliative radiotherapy for the spine. Maximum physical activity should be encouraged, because prolonged immobility exacerbates hypercalcemia. If the aforementioned measures are ineffective, another form of treatment, such as a bisphosphonate, calcitonin, or gallium nitrate, should be considered.
|Disease or patient status||Treatment approach|
|Low-risk disease, age > 70 yr, or major medical problems||Melphalan/prednisone: melphalan, 8 mg/m²/d PO on days 1–4, + prednisone(Drug information on prednisone), 100 mg/d PO on days 1–4|
|High-risk disease, renal failure, or hypercalcemia||VAD: vincristine, 0.4 mg/d IV, + doxorubicin, 9 mg/m²/d IV (both drugs by continuous infusion) on days 1–4, + dexamethasone, 40 mg/d PO on days 1–4, 9–12, and 17–20|
|With spine radiotherapy||Dexamethasone, 40 mg/d PO on days 1–4, 9–12, and 17–20|
|Resistant to melphalan/prednisone|
|Unresponsive||Dexamethasone or VAD (as above)|
|Relapsing||VAD (as above)|
|Resistant to VAD or dexamethasone||Cyclophosphamide, 600 mg/m²/d, + etoposide(Drug information on etoposide), 180 mg/m²/d IV, on days 1–5, + GM-CSF,ª 0.125 mg/m²/d|
|Primary refractory disease < 1 yr (high or intermediate tumor mass)||Myeloablative therapy + blood or marrow stem-cell transplantation|
|ª GM-CSF = granulocyte-macrophage colony-stimulating factor|
Adapted, with permission, from Weber DM, Alexanian R: Multiple myeloma and other plasma cell dyscrasias, in Pazdur R (ed): Medical Oncology: A Comprehensive Review, p 51. Huntington, NY, PRR Inc, 1993.
Renal Failure: Approximately 20% of patients with myeloma present with renal insufficiency , and another 20% will develop this complication during the course of their disease . Casts of Bence Jones protein in the distal tubule are the most common cause of renal failure [29,30], but hypercalcemia, dehydration, and hyperuricemia are also contributing factors . Uncommonly, amyloidosis or light-chain deposition disease may also contribute to renal failure.
Treatment includes hydration, sodium bicarbonate(Drug information on sodium bicarbonate) for acidosis, allopurinol(Drug information on allopurinol) for hyperuricemia, and hemodialysis, if necessary. Plasmapheresis has been proposed by some researchers , but controlled studies have not shown that it yields any improvement in survival. In approximately 50% of previously untreated patients with renal failure, the kidney function normalizes with chemotherapy for the myeloma . VAD therapy for myeloma does not require dose adjustments for renal failure, since none of the drugs is metabolized by the kidneys and VAD provides the best chance for rapid disease control.
Anemia: A normocytic, normochromic anemia is present in 60% of patients at diagnosis . Anemia is due primarily to the decreased production of red blood cells secondary to marrow infiltration with plasma cells. Patients with or without renal failure also have decreased levels of erythropoietin(Drug information on erythropoietin), which may worsen the degree of anemia . Recombinant erythropoietin, 4,000 U given subcutaneously three times a week, may be useful if the serum level of erythropoietin is inappropriately low compared with the hematocrit (eg, less than 200 U/L).
Infection: Many patients with myeloma develop bacterial infections that may be quite serious. In the past, gram-positive organisms (eg, Streptococcus pneumoniae and Staphylococcus aureus) and Hemophilus influenzae have been the most common pathogens, although more recently, gram-negative organisms have become an increasing problem . The increased susceptibility of patients with myeloma to bacterial infection has been attributed to impairments in host-defense mechanisms, which include depressed levels of uninvolved immunoglobulins, impaired antibody response , decreased numbers and adherence of polymorphonuclear leukocytes , decreased surface immunoglobulin expression , poor opsonic activity , depressed lysozyme levels , and decreased complement levels .
A diagnosis of multiple myeloma usually requires the presence of bone marrow plasmacytosis and a monoclonal protein in urine or serum. One class of immunoglobulins is produced in excess, whereas the other immunoglobulin (Ig) classes are depressed. Biclonal elevations of myeloma protein levels occur in less than 1% of cases . The types of monoclonal protein produced are IgG (60%), IgA (20%), IgD (2%), IgE (less than 0.1%), and light-chain kappa or lambda (18%). Fewer than 5% of patients with myeloma are unable to secrete or synthesize light- or heavy-chain immunoglobulins, and their disease is categorized as nonsecretory . The workup should include quantification of both involved and uninvolved immunoglobulins.
After chemotherapy has been instituted, serum and 24-hour urinary measurements of abnormal proteins should be evaluated serially to confirm that the myeloma protein(s) have been reduced markedly in patients who have responded to treatment.
Staging and Prognosis
Different criteria have been used to stage myeloma at different institutions, primarily because of the lack of standard definitions and consistency among investigators (Tables 2 and 3) . This results in part from the imprecise quantification of the extent of bone lesions, hypercalcemia (eg, degree of immobility), and factors other than marrow infiltration that cause anemia (eg, renal failure). Our criteria are outlined in Table 3, which also includes a correlation of pretreatment tumor mass and response with survival time. As expected, the shortest survival occurs in patients with a high tumor mass that is unresponsive, and the longest survival is observed in patients with a low tumor mass that is responsive.
|Stage||Criteria||Myeloma cell mass|
|I||Hemoglobin > 10 g/dL |
Serum calcium = 12 mg/dL or less (normal)
Normal bone or solitary plasmacytoma on x-ray
Low M-component production rates:
IgG < 5 g/dL
IgA < 3 g/dL
M-component < 4 g/24 h
|< 0.6 (low)|
|II||Not fitting stage I or III||0.6–1.20 (intermediate)|
|III||Hemoglobin < 8.5 g/dL |
Serum calcium > 12 mg/dL
Multiple lytic bone lesions on x-ray
High M-component production rates:
IgG > 7 g/dL
IgA > 5 g/dL
M-component > 12 g/24 h
|> 1.20 (high)|
|A||Normal renal function (serum creatinine level < 2.0 µg/dL)|
|B||Abnormal renal function (serum creatinine level = 2.0 mg/dL or more)|
|Adapted from Durie BG, Salmon SE .|
|Stage||Criteria||Myeloma cell mass|
|I||Hemoglobin > 10.5 g/dL |
Corrected serum calcium = 11.5 mg/dL or less
Serum myeloma protein < 4.5 g/dL
|II||Not fitting stage I or III||Intermediate|
|III||Hemoglobin < 8.5 g/dL |
Corrected serum calcium > 12 mg/dL
|Tumor response to therapy||Survival by tumor mass (mo)¹|
²A 50% to 75% reduction of myeloma protein production
Adapted, with permission, from Weber DM, Alexanian R: Multiple myeloma and other plasma cell dyscrasias, in Pazdur R (ed): Medical Oncology: A Comprehensive Review, p 52. Huntington, NY, PRR Inc, 1993.
The level of serum beta-2-microglobulin (beta2M) is an important and convenient prognostic indicator because it reflects the extent of disease in a single measurement. This protein is a catabolic product of the histocompatibility leukocyte antigen that is present on the surface of all nucleated cells and in higher concentration on lymphoid and plasma cells . Because beta2M is excreted by the kidneys, high levels of it are present when renal failure occurs, which complicates the interpretation of a high value. In a study of three staging systems and other variables by Bataille et al, beta2M was the single most important indicator of prognosis .
High serum lactate dehydrogenase (LDH) levels have also been associated with shortened survival (9 months), as well as with drug resistance, in both treated and untreated patients with myeloma [44,45]. Other features associated with an elevated LDH level include lymphoma-like extraosseous disease, plasma-cell leukemia, and plasma-cell hypodiploidy [44,45].
Shortened survival also has been noted in patients with DNA hypodiploidy , low plasma-cell RNA levels , high plasma-cell labeling indices [48,49], plasmablastic histology , and the expression of common acute lymphoblastic leukemia antigen (CALLA) . Patients with decreased plasma-cell RNA or DNA hypodiploidy are also less likely to respond to chemotherapy [46,47].
Because the criteria of response to treatment have varied among institutions, response rates have been difficult to compare. The criteria for partial remission (PR) at M.D. Anderson Cancer Center are a 75% reduction in the rate of myeloma protein production, a 95% reduction in the rate of Bence Jones protein excretion, and less than 5% marrow plasma cells. Bence Jones protein is reduced more rapidly in responders than is serum myeloma protein because of the rapid renal catabolism of light chains. To achieve a complete remission (CR) of disease, there must be disappearance of the M-protein by immunofixation and no monoclonal plasma cells in the bone marrow, as assessed by the most sensitive techniques.
Concurrent with the management of specific complications, chemotherapy should be instituted promptly to reduce the number of malignant plasma cells. However, despite the development of many different chemotherapeutic regimens, there has been little improvement in outcome during the past 25 years. Only 5% to 10% of patients live longer than 10 years, and there is no hint of a cured subgroup [51,52]. The role of chemotherapy will be addressed here separately for patients with newly diagnosed, responsive, primary resistant, or relapsing disease.
Previously Untreated Patients: Since their introduction in the 1960s, intermittent courses of melphalan and prednisone (MP) have been the standard chemotherapy for multiple myeloma . One schedule for this regimen is shown in Table 1. To standardize the absorption differences of melphalan and to ensure its bioavailability, evidence of adequate myelosuppression should be confirmed 2 to 3 weeks after beginning treatment. If the myeloma is unresponsive, the dose should be increased in 20% increments every 4 to 5 weeks until adequate myelosuppression occurs .
The MP combination has been shown to induce a remission in approximately 40% of previously untreated patients . The median remission for these patients has been approximately 2 years, and the median survival has been approximately 3 years. The low frequency of CR (10%) and the inevitable relapse indicate that inherent drug resistance represents the major impediment to long-term remission or cure.
Many attempts have been made to improve the results of MP with combinations, including multiple alkylating agents, vincristine, a nitrosourea, and/or an anthracycline, but none of these agents has proved superior [56-63]. An exception may be the M2 protocol (carmustine [BiCNU], cyclophosphamide(Drug information on cyclophosphamide) [Cytoxan, Neosar], vincristine [Oncovin], melphalan, and prednisone), which showed a better outcome in two studies [64,65], but other studies have failed to confirm this finding [63,66]. Virtually all studies have failed to show a superiority in terms of overall survival, and a recent meta-analysis of these studies showed no overall difference in efficacy .
Combination chemotherapy with VAD-based regimens has also been studied. In one study of newly diagnosed patients, the response rate was 55%, and the onset of remission was more rapid, but there was no improvement in survival over standard regimens . The rapid responses may provide some advantage for patients with hypercalcemia, renal failure, or severe bone pain because such complications must be reversed quickly.
In addition to VAD, dexamethasone alone is as effective as MP for newly diagnosed patients, but the response rate is slightly lower than that with VAD . It remains the most active single agent against myeloma and does not contribute to myelosuppression or secondary myelodysplasia.
Interferon (IFN) inhibits plasma-cell growth and has induced responses in 5% to 10% of patients with refractory myeloma and in 15% of patients with newly diagnosed disease [70,71]. Results of studies with IFN and other agents have varied widely. The combination of IFN with standard regimens of alkylating agents plus a glucocorticoid was no more effective than MP in one study , was associated with a higher response rate and similar survival in another study , and showed a high rate of CR with uncertain survival in a third study . Further clarification of the role of IFN in the primary treatment of multiple myeloma is necessary.
Early myeloablative consolidation therapy supported by autologous bone marrow transplantation (ABMT) also has been investigated [75-77]. A controlled study described significant prolongation of remission and survival when myeloablative therapy followed a primary induction program . However, although the CR and PR rates were higher than those with conventional therapy, so was the frequency of treatment-related deaths. Further studies are necessary to determine the role of early myeloablative treatment and to identify the patient groups who are likely to benefit.
Remission Maintenance: The median remission for responding patients is approximately 2 years. Indefinite maintenance therapy with alkylating agents has not shown prolongation of overall remission or survival compared with no maintenance therapy and the resumption of MP when disease relapse occurs . Patients can experience multiple unmaintained remissions that usually become progressively shorter. Continued alkylating agent treatment also exposes approximately 2% of patients to the risk of acute leukemia [80,81]. Also, it has been shown that the residual tumor cells in remission are less proliferative and more resistant to chemotherapy (cytokinetic resistance) .
The Italian Myeloma Study Group initially reported a superior response duration (26 vs 14 months) with IFN-alfa as a remission treatment compared with no maintenance therapy , but in an updated analysis, no survival benefit was shown . Other studies also have shown no gain in survival and divergent results with regard to remission duration [84-88]. After treatment with high-dose melphalan plus total body irradiation and ABMT, maintenance IFN-alfa was associated with longer remission and survival than no therapy in patients achieving CR . This suggested a possible role for IFN against minimal residual disease (asymptomatic myeloma, solitary plasmacytoma at high risk for progression, or complete remission after chemotherapy). However, IFN is associated with side effects (myalgia, fever, and myelosuppression), is costly, and requires injections. Therefore, further studies are necessary to confirm the role of IFN-alfa as maintenance therapy, especially in direct comparison with melphalan and prednisone.
Relapsing and Refractory Disease: Approximately one half of patients with newly diagnosed multiple myeloma are unresponsive to chemotherapy. In addition, all patients with an initial response will suffer relapse except for the 2% who die of unrelated diseases. For patients whose disease relapses after an unmaintained remission of longer than 6 months, approximately 50% achieve a second, but shorter, remission with resumption of the original therapy .
VAD is the treatment of choice for patients with disease that relapses despite MP treatment. Approximately 40% of patients with relapsing disease responded to this treatment compared with 25% of patients whose disease was unresponsive to primary therapy . Dexamethasone induced similar results in patients with primary resistant disease but was inferior to VAD in patients with relapsing disease . Patients with hypodiploidy or low RNA content of plasma cells were much less likely to respond to treatment. The median duration of remission was 10 months, and subsequent myeloablative consolidation therapy did not result in improved survival .
Resistance to VAD has been attributed in part to the increased expression of p-glycoprotein, the multidrug resistance gene (MDR-1) product that increases the active-transport efflux of certain chemotherapeutic agents (doxorubicin and vincristine) from neoplastic cells [94,95]. Agents that inhibit p-glycoprotein activity, such as verapamil(Drug information on verapamil) and cyclosporine (Sandimmune), have been combined with chemotherapy in an attempt to circumvent such resistance. Both verapamil and cyclosporine administered with VAD have produced modest response rates, in the face of severe toxicity [96,97]. Further studies of newer analogs, such as PSC-833, are currently underway.
High-dose alkylating agents have also been effective in treating VAD-resistant myeloma. Intravenous melphalan, at a dose of 90 to 100 mg/m² (five times the standard dose), has produced responses in one third of such patients, but with a very short remission . A combination of high-dose cyclophosphamide (3 g/m²), etoposide (VePesid, 900 mg/m²), and GM-CSF was also effective in a similar percentage of patients and induced a median remission of 8 months ; high LDH and beta2M levels were indicators of a low response rate and short survival times .
Bone Marrow and Stem-Cell Transplantation: All patients younger than 60 years old who have advanced and resistant myeloma should be considered early for intensive therapy supported by bone marrow or blood stem-cell transplantation. Patients should undergo such therapy with minimal delay to prevent disabling complications that could preclude later treatment.
Only 5% of patients with multiple myeloma are candidates for allogeneic transplantation because of the age restriction (younger than 50 years old) and the availability of a matched sibling donor. Treatments consist of either a combination of one or more alkylating agents with total body irradiation or a combination of high-dose busulfan(Drug information on busulfan) (Myleran)-cyclophosphamide. In the European Bone Marrow Transplant Registry (EBMTR) study, the CR rate was 43% among 90 patients who underwent transplantation and were followed for up to 7 years. The overall survival rate at 5 years was 40%, and the disease-free survival rate was 31% . Similar results have been published by others [102,103]. The sustained disappearance of myeloma protein for more than 5 years has been confirmed in several patients, perhaps due to an additional “graft vs myeloma” effect [100,101]. The available data do not suggest a plateau of disease-free survival, so the potential for curability remains uncertain. Survival was longer for patients who had already responded to treatment prior to the procedure and for patients who had received only one previous regimen. In view of the high mortality rate (approximately 30% to 40% during the first year), this procedure remains a secondary option for selected younger patients with a high benefit/risk ratio.
ABMT in support of myeloablative treatment has been administered more often than allogeneic BMT despite the likelihood of reinfusion of tumor cells with either purged or unpurged marrow . Several investigators showed that high-dose melphalan, either alone or combined with total body irradiation, followed by autologous BMT could produce remission in many patients with recurrent and resistant myeloma . Similar results have been achieved with other intensive regimens, such as a combination of Thiotepa(Drug information on thiotepa) (Thioplex), busulfan, and cyclophosphamide . A sequence of two regimens of high-dose melphalan supported by autologous stem cells has also been used successfully [107,108].
Patients who appear more likely to benefit from myeloablative therapy supported by autologous cell transplantation have become better defined recently [109,110]. Survival was markedly improved among patients with primary resistant disease of less than 1 year's duration (survival equals 83 months) in comparison to similar patients who did not undergo transplantation (37 months). Similarly, myeloablative therapy for patients with a longer duration of primary resistant disease, with disease in resistant relapse, or during remission, showed no meaningful benefit compared with control patients [110,111].
In conclusion, most experts agree that standard myeloablative therapy with autologous bone marrow or blood stem-cell transplantation is not suitable for most patients older than 60 years, with serious or comorbid conditions, or with relapsing disease. The benefit of myeloablative therapy seems most likely in patients with early primary resistant disease, but further studies are necessary to confirm the best treatment groups. Intensive therapy should be administered early before progenitor cells are compromised by prolonged treatment with alkylating agents and before resistance develops.
Other plasma-cell dyscrasias include monoclonal gammopathy of unknown significance, solitary plasmacytoma of bone, asymptomatic myeloma, Waldenström's macroglobulinemia, amyloidosis, and immunoglobulin heavy-chain diseases (Table 4).
|Marrow plasmacytosis > 15%|
Monoclonal immunoglobulin peak (usually > 3.0 g/dL)
Decreased levels of uninvolved immunoglobulins
Bence Jones protein
Lytic bone lesions
|Same as multiple myeloma but without symptoms|
Hemoglobin > 10.5 g/dL
Normal serum calcium level
Monoclonal immunoglobulin (peak < 4.5 g/dL)
|Solitary plasmacytoma of bone|
|Solitary bone lesion due to plasma cell tumor|
Negative skeletal survey and spinal MRI
Negative bone marrow
No anemia, hypercalcemia, or renal disease
Preserved levels of uninvolved immunoglobulins
|Monoclonal gammopathy of unknown significance (MGUS)|
|Monoclonal immunoglobulin level < 3.0 g/dL|
Bone marrow plasma cells = 10% or less
No bone lesions
Usually preserved levels of uninvolved immunoglobulins
|Amyloidosis without myeloma|
|Same as MGUS + evidence of amyloidosis on biopsy|
|Adapted, with permission, from Weber DM, Alexanian R: Multiple myeloma and other plasma cell dyscrasias, in Pazdur R (ed): Medical Oncology: A Comprehensive Review, p 55. Huntington, NY, PRR Inc, 1993.|
Monoclonal Gammopathy of Unknown Significance
Monoclonal gammopathy of unknown significance, or benign monoclonal gammopathy, occurs in 1% of normal individuals older than 40 years. The frequency of this disorder rises progressively with age. No specific underlying diseases have been identified . In a study of 241 patients with this disorder, 53 patients (22%) developed multiple myeloma, macroglobulinemia, amyloidosis, or another malignant lymphoproliferative disorder over a span of 19 years . Multiple myeloma developed in 36 patients after a median interval of 9.6 years. The course of the myeloma and the response to therapy were similar to those of other patients treated promptly after diagnosis. This study demonstrates that monoclonal gammopathy of unknown significance usually does not progress to a malignant disorder. The long period of stability supports the value of indefinite periodic observation for such patients.
Solitary Plasmacytoma of Bone
Approximately 5% of patients with myeloma have a solitary plasmacytoma of bone, and approximately one half demonstrate myeloma protein in serum or urine (Table 4). MRI may reveal abnormalities not detected by bone survey and may cause patients who were previously classified as having solitary plasmacytoma to be upstaged to multiple myeloma . Treatment should include radiation therapy of at least 45 Gy. Patients with solitary plasmacytoma of bone often progress to multiple myeloma, with only 20% to 30% of patients remaining free of disease for more than 10 years [114-116]. When disease progression does occur, the median time for its occurrence is 2 years; however, IFN-alfa may be a useful adjuvant treatment to inhibit the evolution of the disease.
In approximately 20% of patients, multiple myeloma is diagnosed by chance, during screening examinations that reveal an elevated serum protein concentration in asymptomatic patients. Features of low tumor mass are usually present, with a hemoglobin level greater than 10.5 g/dL; serum myeloma protein level less than 4.5 g/dL; and an absence of renal disease, hypercalcemia, and lytic bone lesions . Chemotherapy should be withheld until there is risk of a complication, except for the few patients who present with more advanced disease, who should receive chemotherapy promptly.
Recent studies have defined the prognostic criteria for groups at high risk for early disease progression: a lytic bone lesion, serum myeloma protein level greater than 3 g/dL, and/or Bence Jones protein level greater than 50 mg/d . The presence of a lytic bone lesion and a second high-risk feature predicts progression within 1 year; the absence of these features has been associated with much slower progression (ie, median longer than 5 years).
The results of a French study revealed similar parameters for early disease progression, such as bone marrow plasmacytosis greater than or equal to 25% and a hemoglobin level less than or equal to 12 g/dL . In one study, a plasma-cell-labeling index of more than 0.4% predicted disease progression within 6 months , and in yet another study, 40% of asymptomatic patients were found to have bone marrow involvement on MRI, a feature that also predicted early progression, despite normal skeletal surveys .
Waldenström's macroglobulinemia is an uncommon, low-grade lymphoid malignancy composed of mature plasmacytoid lymphocytes with monoclonal IgM production. It usually affects older persons and may cause symptoms due to tumor infiltration (marrow, lymph nodes, and/or spleen), circulating IgM (hyperviscosity, cryoglobulinemia, and/or cold agglutinin anemia); and tissue deposition of IgM (neuropathy, glomerular disease, and/or amyloidosis)[120-122]. With hyperviscosity syndrome, patients may have visual disturbances, dizziness, cardiopulmonary symptoms, decreased consciousness, and a bleeding diathesis. Neuropathy usually is caused by an IgM antibody reacting with a myelin-associated glycoprotein (MAG)[123,124].
Therapy for hyperviscosity consists of plasmapheresis followed by chemotherapy to control the malignant proliferation. With alkylating agent-steroid combinations, responses occurred in approximately 50% of previously untreated patients, with a median survival of 5 years [125-127]. Cladribine(Drug information on cladribine) (Leustatin) has induced a remission of long duration in more than 80% of previously untreated patients with only two courses of therapy . Cladribine has induced responses in 54% of patients with primary resistant disease and in 83% of patients with relapsing disease occurring while off treatment. Patients whose disease is in resistant relapse are less likely to benefit from such treatment (response rate 18%) and should be considered for more intensive therapies .
Amyloidosis (AL) is a plasma-cell proliferative process that results from organ deposition of amyloid fibrils that consist of the NH2-terminal amino acid residues of the variable portion of the light-chain immunoglobulin molecule. This disease occurs in 10% of patients with multiple myeloma and may produce nephrotic syndrome, cardiomyopathy, hepatomegaly, neuropathy, macroglossia, anemia, carpal tunnel syndrome, and periorbital purpura . Serum immunoelectrophoresis showed a monoclonal immunoglobulin in serum or urine in 89% of patients with amyloidosis . Lambda light chains are more likely than kappa light chains to produce amyloidosis. Diagnosis can be made in many patients by a Congo red-stained sample of subcutaneous fat aspirates or a rectal biopsy that exhibits apple-green birefringence with polarized light.
The median survival is approximately 13 months for all patients, and the presence of congestive heart failure, renal failure, hepatomegaly, and significant weight loss worsens the prognosis [130,131]. An elevated serum creatinine level, the diagnosis of multiple myeloma, the presence of orthostatic hypotension, and a serum M protein had a significant adverse effect on patients who lived 1 year after diagnosis [130,131]. Treatment with colchicine(Drug information on colchicine) has been ineffective, but approximately 15% of patients appear to benefit from MP chemotherapy, and recent reports suggest an even higher response rate of 30% [132,133].
Immunoglobulin Heavy-Chain Diseases
Heavy-chain diseases are plasma-cell dyscrasias characterized by the production of heavy-chain immunoglobulin molecules (gamma, alpha, mu) that lack light chains. Alpha-chain disease results from lymphocyte and plasma-cell infiltration of the mesenteric nodes and small bowel and has features of malabsorption, such as diarrhea, weight loss, abdominal pain, edema, and clubbing . The heavy-chain molecule may be detected in serum, jejunal secretions, and urine.
Patients with gamma heavy-chain disease may present with fever, weakness, lymphadenopathy, hepatosplenomegaly, and Waldeyer's ring involvement. Eosinophilia, leukopenia, and thrombocytopenia are common. Treatment with regimens similar to those used for non-Hodgkin's lymphoma may be effective.
Mu heavy-chain disease is seen exclusively in patients with chronic lymphocytic leukemia. Vacuolated plasma cells are common in the marrow, and many patients have lambda light chains in urine. Therapy is similar to that for chronic lymphocytic leukemia.
There have been many recent advances in the understanding of plasma-cell dyscrasias. The origin of myeloma from a primordial stem cell is suggested by the phenotypic expression of early precursors. Various cytokines are produced that may serve as myeloma cell growth factors or osteoclast-activating factors.
Better understanding of the prognostic factors of myeloma (labeling index), markers of drug resistance, such as LDH; and measures of tumor cell mass, such as beta2M, has helped to identify patients who may benefit from a sequence of VAD followed by the early consideration of myeloablative therapy supported by autologous bone marrow or blood stem-cell transplantation. Melphalan and prednisone appear reasonable for use in older patients and patients with good prognostic features. Certain cytostatic agents, such as IFN-alfa, must be investigated further as part of primary therapy and for remission maintenance. Waldenström's macroglobulinemia and mu heavy-chain disease have been treated with alkylating agents, but cladribine appears promising for superior long-term results. Further studies are needed to understand the etiology and biology of plasma-cell dyscrasias, to develop more effective agents and regimens for controlling these disorders, and to justify immunologic and other procedures for sustaining long-term control.
The authors wish to acknowledge Dr. Raymond Alexanian for his clinical and scientific advice.